: Parkinson's disease (PD) results primarily from striatal dopamine insufficiency and a secondary degeneration of dopaminergic neurons within the substantial nigra pars compacta. The cause of the dopamine (DA) decline still remains unknown. Depending on the age of onset of the disease different risk factors have been identified. Genetic risk is associated with familial cases with early onset. The spontaneous age-related decline in the number of nigral DA cells in humans and non human primates suggests that age is a risk factor for the development of late onset PD. Independent of the age of appearance, DA replacement therapy is the mainstay of therapy. But as PD progresses, drug -related side effects emerge as well as disabling symptoms that are not responsive to the treatment. Since patients with PD have a normal ]lifespan, they must endure crippling systems for many years, severely impacting their quality of life. Clearly, a therapy aimed at stopping the continual loss of DA neurons is needed in order to cease the progression of the disease. In this regard, two experimental strategies have been demonstrated to be successful in animal models of PD; namely administration of the trophic factor glial derived neurotrophic factor (GDNF2 and the administration of antiapoptotic genes such as Bc1-2. Concomitantly with the discovery of genes and proteins that can augment nigrostriatal circuitry is the need to develop ways to deliver them. Indeed, while GDNF is very potent in animal models, a clinicopathological analysis of a PD patient receiving intraventricular (ICV) GDNF found no clinical or neuroanatomical benefit. The method of GDNF delivery likely never reached the vulnerable neurons. In vivo gene therapy approaches are an exciting way to deliver genes in a site-specific manner. We have recently demonstrated that genes can be delivered to the adult monkey brain in a robust, consistent, and sustained fashion without cytotoxicity using a lentiviral vector. We have also tested lentiviral delivery of GDNF into the nigrostriatal system of normal aged rhesus and we observed that this factor is able to reverse the age-related degeneration by increasing the levels of DA and its metabolites in the target areas. The present proposal aims to test the hypothesis that lentiviral gene transfer of Bc1-2 and GDNF can prevent the structural and functional consequences of nigrostriatal degeneration in young and aged MTP-treated monkeys. These studies will serve as the preclinical foundation to determine whether this in vivo method to deliver these potent trophic factor and antiapoptotic genes will be suitable for testing in patients with PD.